JPWO2017183581A1 - Tie2 activation composition - Google Patents

Abstract

Provided is a composition having a Tie2 activation effect, a vascular permeability inhibitory effect, a vascular maturation effect, a vascular normalization effect, a vascular stabilization effect, a lymphatic vessel stabilization effect, and the like. The composition contains one or more components selected from the group consisting of novel iridoid compounds (Compound A, Compound B), oleanoside A, and kaempferol.

Description

  The present invention relates to a composition for activating Tie 2 and the like. More specifically, the present invention contains, as an active ingredient, one or more components selected from the group consisting of novel iridoid compounds (Compound A and Compound B), oleanoside A (Oleanoside A), and kaempferol. The present invention relates to a composition for activating Tie2, a composition for inhibiting vascular permeability, a composition for vascular maturation, a composition for normalizing blood vessels, a composition for stabilizing blood vessels, and a composition for stabilizing lymphatic vessels. The present invention also relates to novel iridoid compounds (Compound A and Compound B) and compositions containing the compounds.

  Olive (Olea europaea) is a plant belonging to the genus Oleaceae, which is widely cultivated in the Mediterranean region, and its fruits are widely used throughout the world for olive oil extraction and food.

  Olive fruits are rich in polyphenols such as hydroxytyrosol, acteoside, oleuropein, etc. (Non-patent Documents 1 and 2), and olive extracts and their polyphenol components have an arteriosclerosis inhibitory action (Non-patent Document 3). ), An antihypertensive effect (Patent Document 1), an inhibitory effect on bone weight loss (Non-Patent Document 4) and the like.

  In recent years, it has been found that aging and functional deterioration of blood vessels affect skin properties such as wrinkles and rough skin, and it is known that the normality of blood vessels is effective as an index for judging skin properties. These blood vessels not only send oxygen and nutrients to the organs throughout the body through the blood, but also carry the waste products from the tissues and excrete them outside the body, which is an important organization for the human body to maintain vital activities. . In general, aging of a blood vessel and failure of a function have a great influence on human health, as represented by arteriosclerosis, and lead to appearances such as wrinkles and swelling. In recent years, activation of the receptor tyrosine kinase Tie2 (Tyrosine kinase with Ig and ECF homology domain 2) has attracted attention against this aging of blood vessels. It is known that when Tie2 is activated by angiopoietin-1 from vascular wall cells, adhesion between vascular endothelial cells is induced and contributes to stabilization of vascular endothelial cells. In recent years, ingredients and foods having this Tie2 activating action have been found, used in supplements and beverages, etc., and used for the purpose of beauty, swelling prevention, cooling prevention, etc. (Patent Documents 2 to 4).

Japanese Patent Laying-Open No. 2005-334022 JP 2014-097977 A JP 2013-241356 A JP 2011-102272 A

J. Agric. Food Chem., Vol.52, pp479-484, 2004 J. Agric. Food Chem., Vol.53, pp8963-8969, 2005, Atherosclerosis, vol.188, No.1, pp35-42, 2006 Clin. Nutr., Vol.25, No.5, 859-868, 2006

  An object of the present invention is to provide a composition having a Tie2 activation effect, a vascular permeability inhibitory effect, a vascular maturation effect, a vascular normalization effect, a vascular stabilization effect, a lymphatic vessel stabilization effect, and the like. For the purpose.

  In order to solve the above-mentioned problems, the present inventors have conducted intensive research. As a result, oleanoside A and kaempferol among components isolated from olive fruit extract have Tie2 activation action, vascular permeability inhibition action, blood vessel It has been newly found to have a maturation action, a blood vessel normalization action, a blood vessel stabilization action, a lymphatic vessel stabilization action and the like. Furthermore, novel iridoid compounds (Compound A and Compound B) are found from the olive fruit extract, and the novel compounds also have Tie2 activation action, vascular permeability inhibition action, vascular maturation action, vascular normalization action, vascular It has been clarified that it has a stabilizing action, a lymphatic vessel stabilizing action, etc., and has completed the present invention.

That is, aspects of the present invention include, but are not limited to, the following inventions.
(1) A compound represented by the following (I), a compound represented by the following (II), a compound represented by the following (III) (Oleanoside A), a compound represented by the following (IV) (Kaempferol), And one or more components selected from the group consisting of salts thereof, and a composition for activating Tie2:


(2) The compound represented by (I), the compound represented by (II), the compound represented by (III) (Oleanoside A), the compound represented by (IV) (Kaempferol), And a composition for suppressing vascular permeability, comprising at least one component selected from the group consisting of salts thereof.
(3) The compound represented by (I), the compound represented by (II), the compound represented by (III) (Oleanoside A), the compound represented by (IV) (Kaempferol), And a composition for vascular maturation, comprising one or more components selected from the group consisting of salts thereof.
(4) The compound represented by (I), the compound represented by (II), the compound represented by (III) (Oleanoside A), the compound represented by (IV) (Kaempferol), And a composition for normalizing blood vessels, comprising one or more components selected from the group consisting of salts thereof.
(5) The compound represented by (I), the compound represented by (II), the compound represented by (III) (Oleanoside A), the compound represented by (IV) (Kaempferol), And a composition for stabilizing a blood vessel, comprising one or more components selected from the group consisting of salts thereof.
(6) The compound represented by (I), the compound represented by (II), the compound represented by (III) (Oleanoside A), the compound represented by (IV) (Kaempferol), And a composition for stabilizing lymphatic vessels, comprising one or more components selected from the group consisting of salts thereof.
(7) The vascular permeability inhibitory action, vascular maturation action, vascular normalization action, vascular stabilization action, or lymphatic vessel stabilization action is due to the Tie2 activation action. (2) -Composition in any one of (6).
(8) The composition according to any one of (1) to (7), which is a food composition.
(9) The composition according to any one of (1) to (7), which is a beverage composition.
(10) Functions exhibited by activating Tie2, functions exhibited by suppressing vascular permeability, functions exhibited by vascular maturation, functions exhibited by normalization of blood vessels, and stabilization of blood vessels The composition according to any one of (1) to (9), which is labeled with one or more functions selected from the group consisting of a function exerted and a function exerted by lymphatic vessel stabilization.
(11) The function indication is “suppresses vascular permeability enhancement”, “suppresses leakage of intravascular factors to the outside of the blood vessel”, “improves blood vessels to a normal state”, “makes blood vessels to a normal state” 1 ”selected from the group consisting of“ maintaining ”,“ suppressing detachment of vascular endothelial cells ”,“ suppressing cell death of vascular endothelial cells ”, and“ maintaining a function of rapidly collecting interstitial fluid ” The composition as described in (10) above.
(12) A compound represented by (I), a compound represented by (II), a compound represented by (III) (Oleanoside A), and a compound represented by (IV) for activation of Tie2. One or more uses selected from the group consisting of the compounds (Kaempferol) and their salts.
(13) The compound represented by (I), the compound represented by (II), the compound represented by (III) (Oleanoside A), the compound represented by (IV) (Kaempferol), And one or more selected from the group consisting of these salts as an active ingredient, a method for activating Tie2.
(14) Formula (I) below
A compound represented by
(15) The following formula (II)
A compound represented by
(16) A composition comprising the compound according to (14) or (15).
(17) A composition comprising the compound according to (14) and (15).
(18) The composition according to (16) or (17), which is a food composition.
(19) The composition according to (16) or (17), which is a beverage composition.

  According to the present invention, a composition containing one or more components selected from the group consisting of novel iridoid compounds (Compound A and Compound B), oleanoside A, kaempferol, and salts thereof as an active ingredient has a Tie2 activating effect. In addition, it can exert a blood vessel permeability inhibitory effect, a blood vessel maturation effect, a blood vessel normalizing effect, a blood vessel stabilizing effect, and a lymphatic vessel stabilizing effect. In addition, by strengthening the connection between vascular endothelial cells due to normalization of blood vessels according to the present invention, nutrition is distributed to the skin through blood vessels, and beauty effects such as improvement of skin firmness and texture and prevention of wrinkles are obtained. It is done. In addition, blood flow is improved by closing the gaps between endothelial cells of blood vessels and lymphatic vessels, and moisture and waste products from the tissues are collected to improve various symptoms such as coldness, stiff shoulders, swelling, and bears. And preventive effect.

FIG. 1 shows the chemical structures of novel iridoid compounds (Compound A and Compound B), oleanoside A, and kaempferol. FIG. 2 shows the purification flow of olive fruit extract. FIG. 3 shows the ¹ H-NMR and ¹³ C-NMR signals of the novel iridoid compound (Compound A) and megaliteractonol. FIG. 4 shows the two-dimensional NMR analysis result of the novel iridoid compound (Compound A). Specifically, as shift correlation spectrum analysis, ¹ H- ¹ H shift correlation two-dimensional NMR ( ¹ H- ¹ H correlation spectroscopy (COSY)) analysis and ¹ H- ¹³ C long range shift correlation two-dimensional NMR ( ¹ H -detected heteronuclear multiple bond connectivity (HMBC)) analysis results. FIG. 5 shows ¹ H-NMR and ¹³ C-NMR signals of the novel iridoid compound (Compound B) and oleanoside A. FIG. 6 shows the two-dimensional NMR analysis result of the novel iridoid compound (Compound B). Specifically, the result of ¹ H- ¹³ C long range shift correlation two-dimensional NMR ( ¹ H-detected heteronuclear multiple bond connectivity (HMBC)) analysis is shown as shift correlation spectrum analysis. FIG. 7 shows the results of comparing the Tie2 activation effects of novel iridoid compounds (Compound A and Compound B), oleanoside A, kaempferol, hydroxytyrosol, and tyrosol with the control group (DMSO). Figure 8 shows the results of evaluating the inhibitory effect of novel iridoid compounds (Compound A and Compound B) on the enhancement of vascular permeability caused by vascular endothelial growth factor (VEGF). Show.

1. Composition
1-1. Composition One embodiment of the present invention is a composition containing, as an active ingredient, one or more components selected from the group consisting of Compound A, Compound B, oleanoside A, kaempferol, and salts thereof. The active ingredient contained in the composition of the present invention is a compound represented by the following formulas (I) to (IV).

  The compounds represented by the formulas (I) and (II) are novel iridoid compounds. The compound of formula (I) is 2- (3,4-dihydroxyphenyl) ethyl (E) -2- (5-ethylidene-2-oxotetrahydropyran-4-yl) acetate (2- (3 , 4-dihydroxyphenyl) ethyl (E) -2- (5-ethylidene-2-oxotetrahydropyran-4-yl) acetate), and may be described as “Compound A” in this specification. The compound of the formula (II) is 2- (3,4-dihydro-3-hydroxymethyl-5-methoxycarbonyl-2-methyl-2H-pyran-4-yl) acetic acid (2- (3,4) 3,4-dihydro-3-hydroxymethyl-5-methoxycarbonyl-2-methyl-2H-pyran-4-yl) acetic acid), and may be described as “Compound B” in this specification. The compound represented by the formula (III) is oleanoside A, and the compound represented by the formula (IV) is kaempferol.

  The compound in the present invention may be in the form of any pharmacologically acceptable salt (including inorganic salts and organic salts). In this specification, “salt” refers to any pharmacologically acceptable salt (including inorganic salts and organic salts), such as sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, hydrochloric acid, and the like. Salt, sulfate, nitrate, phosphate, organic acid salt (acetate, citrate, maleate, malate, oxalate, lactate, succinate, fumarate, propionate, formate Benzoate, picrate, benzenesulfonate, trifluoroacetate, and the like), but is not limited thereto. Salts of the compounds of the invention can be readily prepared by those skilled in the art by any method known in the art.

1-2. Isolation / synthesis of active ingredients contained in the composition of the present invention The active ingredients (Compound A, Compound B, oleanoside A, kaempferol, and / or their salts) contained in the composition of the present invention are derived from natural products. It may be produced by extraction and isolation, or may be produced by a chemical synthesis method, and is not particularly limited. When the active ingredient contained in the composition of the present invention is produced from a natural product, the natural product used as a raw material is not particularly limited, but for example, olive is preferably used. Olive is a plant belonging to the family Asteraceae, and olive fruits can be used as the main raw material, but leaves, seeds, stems, etc. may be mixed. When using olive fruit as a raw material, it may be used as it is or may be dried by freeze-drying or the like. Moreover, the residue after squeezing oil from olive fruit can be used as it is or in a dried state. It is preferable to use only olive juice, which is an aqueous layer obtained by separating a liquid phase obtained from olive fruit into an oil layer and an aqueous layer.

  The variety of olives is not particularly limited, but for example, varieties such as Manzanillo, Lucca, Nevadillo Blanco, Mission, Picual, Arbequina, Ohibranca, Cornicabra, Gordar, Moloioro, Frantoio, Colatina, Retino, etc. can be suitably used. it can.

  Here, in the present invention, “olive fruit juice” refers to an extract obtained from an aqueous layer obtained by separating a liquid phase obtained from an olive fruit extract into an oil layer and an aqueous layer. Olive fruit extract can also be extracted from olives using an aqueous solvent, for example. Examples of the aqueous solvent include water and alcohols (for example, ethanol). For the olive fruit extract, olive juice or an aqueous solvent extract may be used as they are, or an extract obtained by filtering and concentrating polyphenols in an adsorption column and spray-drying them may be used. The olive fruit extract can be obtained through a process of separating and purifying olive fruit. In the olive fruit separation process, the olive fruit that is the raw material is squeezed and separated into oil and fruit juice by centrifugal separation to obtain olive fruit juice. Can do. In the purification step, an extract obtained by filtering and concentrating the olive juice obtained in the separation step can be used as the olive fruit extract in the present invention. In addition, the filtrate obtained by filtration of olive juice is added to a column packed with an adsorption resin to remove components that are not adsorbed to the adsorption resin such as sugars, minerals, and organic acids, and then an aqueous solvent (for example, water, ethanol, etc.). , Or a mixture thereof) may be used as an olive fruit extract. Those skilled in the art can appropriately set the conditions for the type of the adsorbing resin and the column elution solvent according to the variety, form, etc. of the olive used.

  Extraction of an active ingredient contained in the composition of the present invention from a raw material derived from a natural product can be performed using a solvent, but is not limited thereto. Any solvent may be used as long as the active ingredient contained in the composition of the present invention can be extracted, and water, an aqueous solution such as a buffer solution, an organic solvent, or a combination thereof can be used. Any organic solvent may be used as long as it is generally used. For example, alcohols and ketones can be used. Examples of alcohols include lower alcohols (methanol, ethanol, propanol, isopropanol, butanol, isobutanol, etc.) and liquid polyhydric alcohols (1,3-butylene alcohol, propylene glycol, glycerin, etc.). Preferably, hydrous lower alcohols or lower alcohols are used. Examples of ketones include acetone and butanone. Although the usage-amount of a solvent can be suitably set according to the quantity of the raw material to process, the content of the target compound in a raw material, etc., for example, 1.0-1000 mL with respect to 1 g of raw materials, Preferably it is 2 .. 0-500 mL, more preferably 5.0-100 mL of solvent may be used.

  The active ingredient contained in the composition of the present invention can be further purified as necessary after extraction from the raw material to increase the purity. Purification may be performed by any method, for example, by chromatography. Examples of the chromatography include, but are not limited to, ion exchange chromatography, hydrophobic chromatography, hydrophilic chromatography, gel filtration chromatography and the like. The purity of the preparation can be confirmed by high performance liquid chromatography or LC-MS combining high performance liquid chromatography and a mass spectrometer, but is not limited thereto. Furthermore, the chemical structure of the active ingredient contained in the composition of the present invention can be analyzed by nuclear magnetic resonance (NMR), mass spectrum, or the like. The composition of the present invention does not include naturally occurring animals and plants themselves that have not been processed at all.

  When chemically synthesizing an active ingredient contained in the composition of the present invention, the compound of the present invention is produced by appropriately selecting a generally known organic chemistry method using an available compound as a starting material. can do.

1-3. One embodiment of the present invention, such as a composition for activating Tie2, comprises activating Tie2 containing one or more components selected from the group consisting of Compound A, Compound B, oleanoside A, kaempferol, and salts thereof as active ingredients Composition.

  In the present invention, the “composition for activating Tie2” refers to a composition having the ability to convert Tie2 into its active form (phosphorylated Tie2) by phosphorylating. Activation of a receptor called Tie2 present in vascular endothelial cells plays an important role in stabilizing the capillary structure. This Tie2 has been shown to be present not only in vascular endothelial cells but also in lymphatic endothelial cells, activated by angiopoietin-1 released from mural cells, strengthening adhesion between endothelial cells and adhesion with mural cells, Involved in stabilization. It has been reported that the activity of Tie2 decreases with age, for example, and blood vessels and lymphatic vessels are also aged accordingly. Therefore, the Tie2 activation composition in the present invention can prevent and improve aging of blood vessels and lymphatic vessels by the Tie2 activation action.

  In addition, when blood vessel structure becomes unstable due to aging of blood vessels, nutrient components such as plasma components leak from the blood vessels, and necessary components cannot be carried to necessary places. As a result, various troubles such as a decrease in skin condition may occur. Therefore, the Tie2 activating composition in the present invention can stabilize vascular endothelial cells by the Tie2 activating action and exert a blood vessel permeation suppressing action. When the endothelial cells of the blood vessels are tightly connected, nutrition is distributed to the skin, and beauty effects such as improvement of skin firmness and texture, and prevention of wrinkles are obtained. In addition, the gap between endothelial cells in blood vessels and lymphatic vessels is blocked, blood flow is improved, and moisture and waste from the tissue are collected, improving various symptoms such as coldness, stiff shoulders, swelling, and bears. The effect of preventing is obtained. Accordingly, the present invention is a composition for activating Tie2, comprising one or more components selected from the group consisting of Compound A, Compound B, oleanoside A, kaempferol, and salts thereof as an active ingredient, The composition may have a permeability-inhibiting effect, a vascular maturation effect, a vascular normalization effect, a vascular stabilization effect, or a lymphatic vessel stabilization effect.

  As another aspect of the present invention, a composition for suppressing vascular permeability, a composition for vascular maturation, a composition for normalizing blood vessels, a composition for stabilizing blood vessels, a composition for stabilizing lymphatic vessels, and the like can be mentioned. It is done. These compositions preferably contain one or more components selected from the group consisting of Compound A, Compound B, oleanoside A, kaempferol, and salts thereof as active ingredients.

  In the present invention, “inhibition of vascular permeability” refers to suppression of enhancement of vascular permeability caused by VEGF (vascular endothelial growth factor) or the like. “Maturation of blood vessels” refers to the induction of adhesion between vascular endothelial cells and vascular wall cells to form adhesion spots between vascular endothelial cells so that intravascular environmental factors do not easily leak out of the blood vessel. Say. “Normalization of blood vessels” means that the adhesion between vascular endothelial cells is enhanced and the lining of vascular wall cells to vascular endothelial cells is promoted, leading to disordered growth of blood vessels and blood vessels that have broken vascular permeability. This refers to normal abnormal blood vessels. “Stabilization of blood vessels” refers to an action that suppresses damage to existing blood vessels, detachment between vascular endothelial cells, and detachment between vascular endothelial cells and vascular wall cells, and cell death of vascular endothelial cells. . “Lymphatic vessel stabilization” means that the lymphatic vessels are stabilized so that the lymphatic endothelial cells are properly arranged and lined, and the rapid recovery function of interstitial fluid is maintained.

1-4. Content of active ingredient in composition The content of Compound A, Compound B, oleanoside A, kaempferol, and their salts in the composition of the present invention is determined according to the dosage form, administration method, etc. The amount is not particularly limited as long as the desired effect can be obtained. For example, when Compound A is used as an active ingredient, the content of Compound A in the composition of the present invention is 0.01% by weight to 99% by weight, preferably 0.1% by weight to the total amount of the composition. It is 50 wt%, more preferably 1 wt% to 30 wt%, and even more preferably 10 wt% to 30 wt%. When Compound B is used as the active ingredient, the content of Compound B in the composition of the present invention is 0.01% to 99% by weight, preferably 0.1% to 50% by weight, based on the total amount of the composition. %, More preferably 1-30% by weight, and even more preferably 10-30% by weight. When oleanoside A is used as an active ingredient, the content of oleanoside A in the composition of the present invention is 0.01% to 99% by weight, preferably 0.1% to 50% by weight, based on the total amount of the composition. %, More preferably 1-30% by weight, and even more preferably 10-30% by weight. When kaempferol is used as the active ingredient, the kaempferol content in the composition of the present invention is 0.001 to 99% by weight, preferably 0.01 to 50% by weight, based on the total amount of the composition. %, More preferably 0.1 wt% to 30 wt%, and even more preferably 1 wt% to 30 wt%. As used herein, “wt%” means wt% of weight / weight (w / w) unless otherwise specified. Moreover, when various active ingredients exist in forms, such as a salt and a hydrate, the said content shall be calculated, after converting this into a free body (free body).

  The contents of Compound A, Compound B, oleanoside A, kaempferol, and salts thereof can be measured according to methods known to those skilled in the art. For example, using LC-MS / MS, HPLC, etc., it can measure by setting appropriate conditions according to the kind of active ingredient.

1-5. Other components The composition of this invention can contain arbitrary additives and components other than an active ingredient according to the form. Although these additives and / or components are not particularly limited, for example, additives such as excipients, binders, disintegrants, lubricants, antioxidants, preservatives, flavoring agents, flavoring agents, coloring agents, and fragrances. Can be used. For example, L-ascorbic acid, catechin, dextrin, cyclodextrin, calcium carbonate, trehalose and the like can be used. Further, the composition may contain a known component, or may contain a known component that is effective for preventing aging of blood vessels and beauty. For example, Kiraya, twilight, ginkgo, oyster, turmeric, chrysanthemum, jujube, chamomile, butcher bloom, hawthorn, star fruit, ghetto, lotus, rooibos, indian dates, karin, sium Guava, hihatu, siberian carrot, mango ginger, ginseng, akigumi, okahijiki, scallop, ryebu, yabkanzo, jade, honeybee, peony, murabe, salamander, konara, kunugi, akinonoge, shiragamo, oak, biloba Extracts of Nikkei, Sokokushi, Ousei, Gokutiku, Caronin, Vulture, and procyanidins that are effective in improving vascular endothelium, extracts of grape seeds, pine bark, peanut seed coat, lychee seed coat, L-citrulline, L It is possible to use the amino acids such as arginine.

1-6. Applications The composition of the present invention can exhibit various physiological effects as described above. For example, by applying the composition of the present invention, vascular permeability suppression effect, vascular maturation effect, vascular normalization effect, vascular stabilization effect, lymphatic vessel stabilization effect, Tie2 activation effect, etc. are exhibited. As a result, it is possible to obtain a beauty effect such as improvement of skin firmness and texture, prevention of wrinkles, and an improvement and prevention effect such as cooling, stiff shoulders, swelling and bears.

  The composition of the present invention can be applied to either therapeutic use (medical use) or non-therapeutic use (non-medical use). Examples of such compositions include pharmaceuticals (pharmaceutical compositions), foods and beverages (including foods, beverages, food and beverage compositions, food compositions and beverage compositions), and cosmetics (cosmetic compositions). It is not limited to.

  According to a known method, the composition of the present invention is a solid preparation such as a tablet (including a coated tablet), a granule, a powder, a powder, or a capsule, an oral solution, a suspension, an emulsion, a syrup, or It can be provided as an agent formulated into a liquid such as a drink. These agents can be taken as they are or with water or the like. Moreover, although it can use, for example as a raw material of a pharmaceutical or food-drinks after preparing in the form (for example, powder form and granule form) which can be mix | blended easily, it is not limited to this form. In the composition of the present invention, the dosage form as a cosmetic (cosmetic composition) can be arbitrarily selected according to the purpose, and for example, agents such as cream, ointment, emulsion, solution, gel, powder and granule It can be in the form of shapes, packs, lotions, powders and sticks. The preparation forms are also wide-ranging forms such as aqueous solutions, solubilization systems, emulsification systems, powder systems, oil-liquid systems, gel systems, ointment systems, aerosol systems, water-oil two-layer systems and water-oil-powder three-layer systems. can do. That is, if it is a basic cosmetic, face wash, lotion, lotion, milk, cream, gel, essence (beauty serum), pack, mask, massage agent, foundation, lipstick, bath preparation, shampoo, hair conditioner, hair tonic It can be widely used in forms such as ointments, pastes, and sheet products (absorbent articles such as sanitary products, wiping wipes, and wet tissues). And it is not limited to the dosage form and form of this invention. In addition, in making these dosage forms, various oil agents, surfactants, gelling agents, preservatives, antioxidants, solvents, alcohol, water, chelating agents, thickeners, ultraviolet absorbers, emulsion stabilizers, pH A regulator, a pigment, a fragrance, and the like can be appropriately blended.

  Specific examples of the beverage of the present invention include oolong tea beverage, black tea beverage, green tea beverage, fruit juice beverage, vegetable juice, sports drink, isotonic beverage, enhanced water, mineral water, near water, nutritional drink, beauty drink, or various Examples include alcoholic beverages.

  Moreover, the drink of this invention is made into a container stuffed drink through processes, such as sterilization, as needed. For example, a sterilized container-packed beverage can be produced by a method of performing heat sterilization after filling a beverage into a container, or a method of sterilizing a beverage and then filling the container in an aseptic environment.

  The type of container used for the container-packed beverage is not particularly limited. For example, a plastic container such as a plastic bottle, a paper container such as a paper pack, a glass container such as a glass bottle, a metal container such as an aluminum can or a steel can, an aluminum pouch Any container that is usually used for beverages can be used.

  The food or drink of the present invention is not particularly limited. For example, health foods, functional foods (including special health foods, conditional special health foods, nutritional functional foods, functional indication foods), special foods, or Examples include health supplements. Content of the said active ingredient in the food / beverage products of this invention is as having mentioned above about the composition.

  For example, when preparing a known food or drink, the food or drink of the present invention may be prepared according to a known method for producing a food or drink by mixing a predetermined amount of the active ingredient with the raw materials. You may prepare by adding the said active ingredient to a well-known food / beverage product so that it may become the said predetermined amount. In addition, a well-known food / beverage product may contain the said active ingredient originally, and if the said active ingredient becomes the said predetermined amount, it can mix | blend and prepare suitably.

  The composition of the present invention can be applied by an appropriate method according to the form. The application method is not particularly limited as long as the active ingredient according to the present invention can be transferred into the circulating blood. For example, it may be in the form of oral solid preparations, oral liquid preparations such as oral liquids or syrups, or parenteral preparations such as injections, external preparations, suppositories or transdermal absorption agents, etc. It is not limited to. In this specification, “application” is used to include all aspects such as ingestion, taking, drinking, and transdermal absorption. The application amount of the composition of the present invention is set in a timely manner according to its form, administration method, purpose of use, and age, weight, and symptom of the patient or animal to be administered, and is not constant. The effective human intake of the composition of the present invention is not constant and is not particularly limited. The effective human intake of the composition of the present invention is, for example, 0.1 mg to 400 mg (0.002 mg / kg to 8 mg / kg), preferably 1 mg to 300 mg (0.02 mg / kg) per day for a human weighing 50 kg. -6 mg / kg), more preferably 10 mg to 200 mg (0.2 mg / kg to 4 mg / kg). The composition of the present invention may be applied once or several times within one day within a desired intake range. The application period is also arbitrary. The effective human intake of the composition of the present invention refers to the intake of the composition of the present invention that exhibits an effective effect in humans, and the type of active ingredient contained in the composition is not particularly limited.

  The subject of application of the composition of the present invention is preferably a human, but domestic animals such as cattle, horses and goats, pet animals such as dogs, cats and rabbits, or experimental animals such as mice, rats, guinea pigs and monkeys. It may be. When an animal other than a human is applied to a subject, the daily application amount per mouse (about 20 g) is a condition such as the content of an active ingredient in the composition, the state of the application subject, body weight, sex and age. For example, it is 0.002 mg / kg to 8 mg / kg, preferably 0.02 mg / kg to 6 mg / kg, more preferably 0.2 mg / kg to 4 mg / kg. In another aspect of the present invention, the indication of the function exerted by suppressing vascular permeability, vascular maturation, vascular normalization, vascular stabilization, lymphatic vessel stabilization, or Tie2 activation is provided. The present invention relates to a composition containing the agent of the present invention. Such display or function display is not particularly limited. For example, “suppresses increase in vascular permeability”, “suppresses leakage of intravascular factors to the outside of blood vessels”, “improves blood vessels to a normal state”. , “Maintaining blood vessels in a normal state”, “suppressing detachment between vascular endothelial cells”, “suppressing cell death of vascular endothelial cells”, or “maintaining a rapid recovery function of interstitial fluid” Or a display or a function display that can be equated with these. In the present specification, such indications and indications such as function indications may be attached to the composition itself, or may be attached to the container or packaging of the composition.

2. Use for Activating Tie2 One aspect of the present invention is the use of one or more selected from the group consisting of Compound A, Compound B, oleanoside A, kaempferol, and salts thereof for inhibiting vascular permeability, Use for maturation, blood vessel normalization, blood vessel stabilization, lymphatic vessel stabilization, or Tie2 activation, preferably use for Tie2 activation.

  In addition, by using Tie2 by using the present invention, a blood vessel permeability suppressing effect, a blood vessel maturation effect, a blood vessel normalizing effect, a blood vessel stabilizing effect, a lymphatic vessel stabilizing effect, etc. are obtained. You can also. The use is in a human or non-human animal and may be therapeutic or non-therapeutic. Here, “non-therapeutic” is a concept that does not include a medical act, that is, a treatment act on the human body by treatment.

3. Method of activating Tie2 One aspect of the present invention is a Tie2 activation method using one or more selected from the group consisting of Compound A, Compound B, oleanoside A, kaempferol, and salts thereof as an active ingredient. is there. Specifically, one aspect of the present invention provides a method for activating Tie2, comprising administering a therapeutically effective amount of the active ingredient to a subject in need of Tie2 activation. The target requiring Tie2 activation is as described above for the composition.

  In one embodiment of the present invention, one or more selected from the group consisting of Compound A, Compound B, oleanoside A, kaempferol, and salts thereof is used as an active ingredient. It is also a method for normalizing blood vessels, stabilizing blood vessels, or stabilizing lymphatic vessels.

  Further, in this specification, the therapeutically effective amount is taken when one or more selected from the group consisting of Compound A, Compound B, oleanoside A, kaempferol, and salts thereof are ingested by the subject. This is the amount of Tie2 activation that can be obtained compared to a non-existing subject. The specific effective amount is appropriately set depending on the administration form, administration method, purpose of use, age, weight, symptom, etc. of the subject and is not constant.

  In the method of the present invention, the active ingredient may be administered as it is or as a composition containing the active ingredient so that the therapeutically effective amount is obtained.

4). Novel iridoid compound One embodiment of the present invention is a novel iridoid compound represented by the following formula (I) or (II).

  The compound of the formula (I) is an IUPAC name 2- (3,4-dihydroxyphenyl) ethyl (E) -2- (5-ethylidene-2-oxotetrahydropyran-4-yl) acetate (2- (3,4-dihydroxyphenyl) ethyl (E) -2- (5-ethylidene-2-oxotetrahydropyran-4-yl) acetate), and may be described as “Compound A” in this specification. The compound of the formula (II) is 2- (3,4-dihydro-3-hydroxymethyl-5-methoxycarbonyl-2-methyl-2H-pyran-4-yl) acetic acid (2- (3,4) 3,4-dihydro-3-hydroxymethyl-5-methoxycarbonyl-2-methyl-2H-pyran-4-yl) acetic acid), and may be described as “Compound B” in this specification.

  The compound in the present invention may be in the form of any pharmacologically acceptable salt (including inorganic salts and organic salts). In the present specification, the “salt” is not particularly limited as long as it is a pharmacologically acceptable salt (including inorganic salt and organic salt) as described above. For example, sodium salt, potassium salt, calcium Salt, magnesium salt, ammonium salt, hydrochloride, sulfate, nitrate, phosphate, organic acid salt (acetate, citrate, maleate, malate, oxalate, lactate, succinate, fumarate Acid salt, propionate, formate, benzoate, picrate, benzenesulfonate, trifluoroacetate, etc.). Salts of the compounds of the invention can be readily prepared by those skilled in the art by any method known in the art.

4-1. Production Method of Novel Iridoid Compound The novel iridoid compound (Compound A, Compound B) of the present invention may be produced by extraction and isolation from a natural product, or may be produced by a chemical synthesis method, and is not particularly limited. When producing from a natural product, the natural product used as a raw material is not particularly limited, but it is particularly preferable to use olive. Olive is a plant belonging to the family Asteraceae, and olive fruits can be used as the main raw material, but leaves, seeds, stems, etc. may be mixed. When using olive fruit as a raw material, it may be used as it is or may be dried by freeze-drying or the like. Moreover, the residue after squeezing oil from olive fruit can be used as it is or in a dried state. It is preferable to use only olive juice, which is an aqueous layer obtained by separating a liquid phase obtained from olive fruit into an oil layer and an aqueous layer. “Olive” and “olive juice” are as described above for the composition.

  Extraction of the novel iridoid compound of the present invention from a natural product-derived raw material (for example, olive fruit extract) can be performed using a solvent, but is not limited thereto. Any solvent may be used as long as the active ingredient contained in the composition of the present invention can be extracted, and water, an aqueous solution such as a buffer solution, an organic solvent, or a combination thereof can be used. Any organic solvent may be used as long as it is generally used. For example, alcohols and acetone can be used. Examples of alcohols include lower alcohols (methanol, ethanol, propanol, isopropanol, butanol, isobutanol, etc.) and liquid polyhydric alcohols (1,3-butylene alcohol, propylene glycol, glycerin, etc.). Preferably, hydrous lower alcohols or lower alcohols are used. Although the usage-amount of a solvent can be suitably set according to the quantity of the raw material to process, the content of the target compound in a raw material, etc., for example, 1.0-1000 mL with respect to 1 g of raw materials, Preferably it is 2 .. 0-500 mL, more preferably 5.0-100 mL of solvent may be used.

  The novel iridoid compound of the present invention can be further purified to enhance its purity after extraction from the raw material, if necessary. Purification may be performed by any method, for example, by chromatography. Examples of the chromatography include, but are not limited to, ion exchange chromatography, hydrophobic chromatography, hydrophilic chromatography, gel filtration chromatography and the like. The purity of the preparation can be confirmed by high performance liquid chromatography or LC-MS combining high performance liquid chromatography and a mass spectrometer, but is not limited thereto. Furthermore, the chemical structure of the novel iridoid compound of the present invention can be analyzed by nuclear magnetic resonance (NMR), mass spectrum, and the like.

  When the novel iridoid compound of the present invention is chemically synthesized, a desired compound can be produced by appropriately selecting a generally known organic chemistry method using an available compound as a starting material.

4-2. Composition One embodiment of the present invention is a composition containing Compound A and / or Compound B. As described above, Compound A and Compound B, which are the novel iridoid compounds of the present invention, have various physiological actions, such as Tie2 activation action, vascular permeability inhibitory action, vascular maturation action, and vascular normalization action. , Stabilizing action of blood vessels, stabilizing action of lymphatic vessels and the like. Therefore, the composition of the present invention, in one aspect, has a Tie2 activation action, a vascular permeability inhibitory action, a vascular maturation action, a vascular normalization action, a vascular stabilization action, or a lymphatic vessel stabilization action. It is what you have. Examples of the composition include pharmaceuticals (pharmaceutical compositions), food and drink (food, beverages, food and beverage compositions, food compositions and beverage compositions), cosmetics (cosmetic compositions), and the like. However, it is not limited to these.

  Compound A and / or Compound B contained in the composition of the present invention may be produced by extraction and isolation from natural products as described above, or may be produced by a chemical synthesis method, and is not particularly limited. When the active ingredient contained in the composition of the present invention is produced from a natural product, the natural product used as a raw material is not particularly limited, but for example, olive is preferably used. The method for isolating and synthesizing Compound A and / or Compound B is also as described above. It should be noted that the composition of the present invention does not include those that are not processed at all by naturally occurring animals and plants, or those that are not extracted with other components.

  The content of Compound A and / or Compound B in the composition of the present invention is not particularly limited. For example, the content of Compound A in the composition of the present invention is 0.01% by weight relative to the total amount of the composition. ~ 99 wt%, preferably 0.1 wt% to 50 wt%, more preferably 1 wt% to 30 wt%, even more preferably 10 wt% to 30 wt%, The content of is 0.01% to 99% by weight, preferably 0.1% to 50% by weight, more preferably 1% to 30% by weight, and still more preferably relative to the total amount of the composition. 10% by weight to 30% by weight. The other components that can be blended in the composition are as described above.

  Hereinafter, the present invention will be described more specifically based on examples. The present invention is not limited to these examples.

Example 1: Determination of structure of Compound A and Compound B
1-1. Preparation of olive fruit extract Olive fruit is squeezed, centrifuged, and separated into oil and fruit juice. After filtering the olive juice obtained here, the non-adsorbed components such as sugars, minerals, and organic acids such as saccharides, minerals, and organic acids are removed using an adsorption system column, and the water-containing alcohol eluate is concentrated and spray dried. Used as an extract. Subsequently, this fruit extract (500 g) was subjected to column chromatography using Diaion HP20 (resin amount: 10 L, elution solvent: ethanol: water (0: 100 → 70: 30)) to fractionate the olive fruit extract. Each fraction was obtained as follows (Fr. 1: 179 g, Fr. 2: 120 g, Fr. 3: 85 g, Fr. 4: 71 g, Fr. 5: 26 g). Among the fractions in which Tie2 activity was observed in Fr.1 to Fr.5, Fr.4 (50% ethanol elution part, 20 g) was subjected to column chromatography using Toyopearl HW-40C (resin amount; 500 mL, elution) Solvent: methanol: water (10: 90 → 70: 30) → acetone: water (70:30)) was performed, and Fr.4 was fractionated into 19 fractions (Fr.4a to Fr.4s). The fraction Fr.4k in which Tie2 activity was observed in Fr.4a to Fr.4s was subjected to preparative HPLC (Preparative HPLC) under the following analysis condition 1, and further divided into 6 fractions (Fr.4ka to 4kf). Among the fractions with the highest Tie2 activity observed between Fr.4ka and Fr.4kf, Fr.4kb and Fr.4kd were purified using preparative HPLC under the following analytical conditions 2 and 3. Compound A (46.2 mg), Compound B (19.5 mg) and Oleanoside A (98.1 mg) were isolated. In addition, Fr.4r in which Tie2 activity was observed was also subjected to preparative HPLC (Preparative HPLC) under analysis condition 4 to isolate Kaempferol (3.7 mg). FIG. 2 shows a purification flow of olive fruit extract.

<Analysis condition 1>
Detection: 220 nm
Flow rate: 15 mL / min
Column: Capcell Pack C18 TYPE AQ φ3.0 × 25.0 cm (SHISEIDO)
Mobile phase: CH ₃ CN: H ₂ O (32:68)
Column temperature: Room temperature 25 ° C
<Analysis condition 2>
Detection: 220 nm
Flow rate: 10 mL / min
Column: TSK-Gel Amide-80 φ2.15 × 30.0 cm (TOSOH)
Mobile phase: CH ₃ CN: H ₂ O (0 min, 100: 0 → 15 min, 100: 0 → 20 min, 80: 20 → 35 min, 80:20)
Column temperature: Room temperature 25 ° C
<Analysis condition 3>
Detection: 220 nm
Flow rate: 10 mL / min
Column: COSMOSIL Cholester φ2.0 × 25.0 cm (nacalai tesque)
Mobile phase: CH ₃ CN: H ₂ O (20:80)
Column temperature: Room temperature 25 ° C
<Analysis condition 4>
Detection: 280 nm
Flow rate: 15 mL / min
Column: Capcell Pack C18 TYPE AQφ3.0 × 25.0 cm (SHISEIDO)
Mobile phase: CH ₃ CN: H ₂ O (27:73)
Column temperature: Room temperature 25 ° C

1-2. Structural analysis of Compound A
Compound A was obtained as a colorless oily substance, and the result of high-resolution electrospray-ionization mass spectrometry (HRESI-MS) revealed that it had the molecular formula C ₁₇ H ₂₀ O ₆ . From the UV spectrum pattern (λmax 282), it was speculated that this compound has a benzene ring in the molecule. Next, in ¹ H-nuclear magnetic resonance ( ¹ H-NMR), one set of ABX signals [δ _H : 6.62 (1H, dd, J = 2.0, 8.0 Hz), 6.74 (1H, d, J = 2.0 Hz ), 6.82 (1H, d, J = 8.0 Hz)] and eight peak patterns observed in ¹³ C-NMR (δ _c : 34.6, 66.0, 115.5, 116.4, 121.3, 130.7, 143.5, 143.6) suggested the presence of hydroxytyrosol. Further, in ¹ H-NMR, one methyl-derived signal, three methylene-derived signals, one methine-derived signal, and one olefinic proton were confirmed. ^{In 13} C-NMR, when units other than hydroxytyrosol were confirmed, one methyl-derived signal, three methylene-derived signals, two methine-derived signals, and three quaternary carbon-derived signals were confirmed. Subsequently, in order to clarify these bonding modes, ¹ H- ¹ H correlation spectroscopy ( ¹ H- ¹ H COZY), ¹ H-detected multiple quantum coherence (HMQC), ¹ H-detected multiple-bond connectivity ( When HMBC) was measured and analyzed in detail, it was revealed that the structure of this unit is a compound characterized by iridoids. The iridoid unit whose structure was clarified this time by detailed analysis of spectral data centered on two-dimensional NMR with reference to an example of the isolation report of iridoids derived from olives is that the hydroxyl group at the 3-position of megalactanol is a carboxyl group. Clarified that the structure was converted.

Subsequently, when HMBC was analyzed to examine the binding mode of each unit, the correlation from the proton at the 8 ′ position of the hydroxytyrosol unit to the carbonyl carbon at the 3rd position of megaretactanol was confirmed. It was revealed that the 8'-position of hydroxytyrosol and the 3-position of megalactanol were ester-bonded. The structure of Compound A was determined from the above spectral data. FIG. 3 shows the ¹ H-NMR and ¹³ C-NMR signals of Compound A and megalactanol. Also, Figure 4 shows the results of two-dimensional NMR analysis of ^{Compound A (1 H- 1 H correlation} spectroscopy (COSY) analysis and ^{1 H-detected heteronuclear multiple bond connectivity} (HMBC) analysis).

1-3. Structural analysis of Compound B
Compound B was obtained as a colorless oil. ^{In 1} H-NMR, ^one methyl group-derived signal, two methylene group-derived signals, two methine group-derived signals, one methoxy group-derived signal, and one olefin-derived signal were confirmed. ^{In 13} C-NMR, two methyl groups (δ _c : 19.4, 51.5), two methylene groups (δ _c : 38.2, 62.3), and four methine groups (δ _c : 29.6, 45.0, 74.1, 156.2) ) Three quaternary carbons (δ _c : 108.5, 169.3, 174.3), a total of 11 carbon signals were confirmed. Since the above ¹ H-NMR and ¹³ C-NMR results and UV absorption could not be confirmed, this compound was presumed to be iridoids. Next, two-dimensional NMR ( ¹ H- ¹ H COZY, HMQC, HMBC) was analyzed for the purpose of confirming these binding modes, and the structure of this compound was clarified. The structure clarified by the above analysis is similar to the oleanosides reported as one of the components of olive fruit, and comparing their spectral data, the signals at the 6th, 7th and 8th positions are compared. It was confirmed that there was a good correlation except for. In addition to the above results, the structure of Compound B was determined based on the fact that the present compound could not confirm the HMBC correlation from the 8-position methylene to the 7-position carbonyl carbon and the molecular weight results obtained by MS. . The ¹ H-NMR and ¹³ C-NMR signals of Compound B and oleanoside A are shown in FIG. In addition, FIG. 6 shows the results of two-dimensional NMR analysis ( ¹ H- ¹ H correlation spectroscopy (COSY) analysis and ¹ H detected heteronuclear multiple bond connectivity (HMBC) analysis) of Compound B. Oleanoside A and Keampferol were identified after comparison with literature values described in the paper.

Example 2: Evaluation of Tie2 activation action
Compound A and Compound B were dissolved in a serum vascular endothelial cell growth medium (Humedia-EG2 manufactured by Kurashiki Boseki Co., Ltd.) so that the final concentration was 10 μg / mL to prepare a test sample. In addition, a test sample in which Angiopoietin-1 was dissolved in Humedia-EG2 to a concentration of 500 ng / mL was prepared and used as a positive control.

Next, normal human umbilical vein endothelial cells (HUVEC) cultured to confluence were seeded in a 96-well plate at 2.0 × 10 ⁴ cells / 0.1 mL / well and cultured overnight using Humedia-EG2. The HUVEC after overnight culture was replaced with 0.1 mL of vascular endothelial cell basal medium (Humedia-EB2 manufactured by Kurashiki Boseki Co., Ltd.) 3 hours before cell stimulation (addition of test sample), and culture was performed again. Thereafter, 0.1 mL of the test sample was added to the well and incubated for 20 minutes. After incubation, the amount of phosphorylated Tie2 in the cells was measured using an immunoassay kit (R & D Systems, Human Phospho-Tie2 (Y992) Immunoassay) according to the protocol. As a negative control, phosphorylated Tie2 was similarly measured for dimethyl sulfoxide (DMSO) used to dissolve the test sample. Then, the activation rate of Tie2 was calculated according to the following formula, and the phosphorylation action was evaluated.

  Tie2 activation rate (%) = measured value of phosphorylated Tie2 when test sample is added / measured value of phosphorylated Tie2 in negative control) x 100

  The results are shown in Table 1 and FIG. As shown in Table 1 and FIG. 7, Tie2 activation action was confirmed in Compound A, Compound B, oleanoside A, and kaempferol.

Example 3: Inhibition of vascular permeability of Compound A and Compound B Using the DMSO solution (25 μM) of Compound A or B prepared in Example 1 as a test sample, vascular endothelial growth factor (vascular endothelial factor) The inhibitory effect on the increase in vascular permeability caused by endothelial growth factor (VEGF) was evaluated using the Miles assay method. This animal experiment was conducted based on the plan approved by the head of the institution after reviewing the Animal Protection Committee and other related laws and regulations, and after review by the in-house animal experimentation committee.

3-1. Test method
Eight weeks old Balb / c female mice were preliminarily kept for more than one week, then eight administration sections were set per animal (four on the left and right sides of the back midline) and evaluated at n = 6 did.

  15 minutes after intravenous administration of 100 μL of 1% Evans Blue dye prepared in physiological saline under anesthesia, VEGF (final concentration: 300 ng / mL) and each test sample were mixed in equal amounts, and 15 μL of that was added to the dorsal skin Administered. Forty minutes after intradermal administration, the dye leaked into the skin was extracted with 500 μL of formamide, and the amount of dye was quantified by absorbance at 620 nm. A section in which neither VEGF nor the test sample was administered and a section in which only VEGF was administered were provided at the same time. Dunnett's multiple comparison test was used for the significance test.

3-2. The amount of Evans Blue dye leaked as a result is shown in FIG. The inhibition rate of vascular permeability by the test sample was 89% for Compound A and 139% for Compound B. As mentioned above, the action which suppresses the permeability | transmittance from a blood vessel was confirmed about both Compound A and Compound B.

  The present invention provides a composition having a Tie2 activation effect, a vascular permeability inhibitory effect, a vascular maturation effect, a vascular normalization effect, a vascular stabilization effect, a lymphatic vessel stabilization effect, etc. It is. Thus, this invention provides the new composition etc. which have preferable physiological activity, and can utilize it for food-drinks etc.

Claims (19)

Compounds represented by the following (I), compounds represented by the following (II), compounds represented by the following (III) (Oleanoside A), compounds represented by the following (IV) (Kaempferol), and those A composition for activating Tie2 containing one or more components selected from the group consisting of salts:
  The compound represented by (I), the compound represented by (II), the compound represented by (III) (Oleanoside A), the compound represented by (IV) (Kaempferol), and their A composition for suppressing vascular permeability, comprising one or more components selected from the group consisting of salts.   The compound represented by (I), the compound represented by (II), the compound represented by (III) (Oleanoside A), the compound represented by (IV) (Kaempferol), and their A composition for vascular maturation comprising one or more components selected from the group consisting of salts.   The compound represented by (I), the compound represented by (II), the compound represented by (III) (Oleanoside A), the compound represented by (IV) (Kaempferol), and their A composition for normalizing blood vessels, comprising one or more components selected from the group consisting of salts.   The compound represented by (I), the compound represented by (II), the compound represented by (III) (Oleanoside A), the compound represented by (IV) (Kaempferol), and their A composition for stabilizing a blood vessel, comprising one or more components selected from the group consisting of salts.   The compound represented by (I), the compound represented by (II), the compound represented by (III) (Oleanoside A), the compound represented by (IV) (Kaempferol), and their A composition for stabilizing a lymphatic vessel, comprising one or more components selected from the group consisting of salts.   The vascular permeability inhibitory action, vascular maturation action, vascular normalization action, vascular stabilization action, or lymphatic vessel stabilization action is caused by the Tie2 activation action. The composition according to any one of the above.   The composition according to any one of claims 1 to 7, which is a food composition.   The composition according to any one of claims 1 to 7, which is a beverage composition.   Functions exhibited by activating Tie2, functions exhibited by suppression of vascular permeability, functions exhibited by vascular maturation, functions exhibited by normalization of blood vessels, and exhibited by stabilization of blood vessels The composition according to any one of claims 1 to 9, which is labeled with one or more functions selected from the group consisting of functions and functions exhibited by lymphatic vessel stabilization.   The function display is “suppresses vascular permeability enhancement”, “suppresses leakage of intravascular factors outside the blood vessel”, “improves blood vessels to a normal state”, “maintains blood vessels to a normal state” , One or more selected from the group consisting of “suppressing divergence between vascular endothelial cells”, “suppressing cell death of vascular endothelial cells”, and “holding a function of rapidly collecting interstitial fluid” The composition according to claim 10.   The compound represented by (I), the compound represented by (II), the compound represented by (III) (Oleanoside A), and the compound represented by (IV) for activating Tie2 (Kaempferol) and one or more uses selected from the group consisting of their salts.   The compound represented by (I), the compound represented by (II), the compound represented by (III) (Oleanoside A), the compound represented by (IV) (Kaempferol), and their A method for activating Tie2, wherein one or more selected from the group consisting of salts is used as an active ingredient. Formula (I)
A compound represented by The following formula (II)
A compound represented by   A composition comprising the compound according to claim 14 or 15.   A composition comprising the compound according to claim 14 and 15.   The composition according to claim 16 or 17, which is a food composition.   The composition according to claim 16 or 17, which is a beverage composition.